Type-I IFNs in EAE drive synaptic transcriptional responses in neurons and astrocytes in the brain

Abstract

Neuronal pathology plays a prominent role in the cognitive and neuropathic symptoms of multiple sclerosis; however, little is known about these pathological signals to neurons in the brain and their consequences on cognition. Here, using a transgenic reporter of IFN signaling with spatial RNA-sequencing, we determined myelin-specific autoimmune T cells enter the brain parenchyma through the interface between the fimbria and third ventricle. Here, astrocytes and microglia express high levels of MHC-II-associated transcripts. Using this reporter, we also showed microglia within the brain are not direct responders of IFNs, but express transcripts associated with synaptic pruning, potentially contributing to pathological remodeling of neuronal circuits. Moreover, both type-I and type-II IFNs are required for T cells to infiltrate the brain and initiate an IFN response associated with synaptic and metabolic programs in neurons and astrocytes in the cortex and hippocampus. In summary, this study elucidates multiple steps of the pathogenesis of EAE pathology within the brain independent of the spinal cord. IFNs activate astrocytes and neurons in EAE brain Summary Autoreactive T cells in EAE activate IFN-responsive pathways in neurons and astrocytes in the brain. T cells enter the brain through the fimbria and drive transcriptional signatures of synaptic dysfunction in neurons and synaptic pruning in microglia.